Rapamycin is effective in inhibiting the growth of both mouse and human lung cancer cells. FTI exhibited a significant efficacy against lung tumorigenesis using both chemopreventive and therapeutic protocols in A/J mice. Recent studies have linked the mammalian target of rapamycin (mTOR) and Rheb (Ras homology enriched in brain, a target of FTI) together as key components of the TSC-Rheb-mTOR pathway. We hypothesize that rapamycin and FTI are potent chemopreventive agents in a mutant lung cancer model and the combination of rapamycin and FTI will have a synergistic effect in chemoprevention of lung cancer. Specific aims include: (1) To evaluate the effect of rapamycin and FTI on lung adenocarcinoma carcinogenesis in a transgenic mouse lung carcinoma model with genetic changes commonly seen in human lung cancers; (2) To examine the chemopreventive efficacy of rapamycin and FTI against tumorigenesis in TSC knockout mice; (3) To investigate the mechanism of rapamycin and FTI's chemopreventive efficacy against lung cancer in mice. This proposal is timely and significant for the following reasons. Firstly, clinical chemoprevention trials of mTOR inhibitor and FTI against lung cancer will require vigorous preclinical characterizations of their efficacy and mechanism(s). In particular, clinical relevant compounds (CCI-779 for rapamycin and R115777 for FTI) will be used in this proposal. Secondly, we will use a newly developed mutant mouse lung tumor model, which shares both histopathologicalfeatures and genetic alterations (activated oncogenes and inactivated tumor suppressors) observed in human lung adenocarcinogenesis. And thirdly, we will conduct comprehensive animal bioassays to test the combinatorial efficacy of rapamycin + FTI to significantly increase the efficacy and lowering potential toxicity of these agents in preventing lung cancer. The results from this proposal will provide significant insights on how mTOR inhibitor and FTI synergistically affect the mTOR signaling pathway during mouse lung tumorigenesis. In addition, this proposal will provide a solid foundation for clinical trials of mTOR inhibitor and FTI as lung cancer chemopreventive agents.